Investigation of oral macrolide prescriptions in Japan using a retrospective claims database, 2013–2018

Macrolide usage in Japan exceeds that in Europe and the United States. Investigating the actual conditions in which macrolides are used is important for identifying further interventions for appropriate antimicrobial use; however, this situation has not been evaluated in Japan. Therefore, we aimed to clarify the number of macrolide prescriptions and their changes before and after implementation of the Antimicrobial Resistance (AMR) Action Plan. In addition, we also investigated the names of diseases for which macrolides have been prescribed and the number of days of prescription. A retrospective observational study was conducted using JMDC claims data from January 2013 to December 2018. The proportion of all oral antimicrobials and macrolides used during this period and the diseases for which macrolides were used in the 3 years before and after the AMR Action Plan were determined separately for acute (< 14 prescription days) and chronic (> 14 prescription days) diseases. The number of prescriptions for macrolides constituted approximately 30% of those for all oral antimicrobials; of these, clarithromycin accounted for approximately 60%. Most prescriptions for acute diseases were for common cold, whereas allergic and dermatological diseases were included among chronic diseases. The names of these illnesses did not change before and after the AMR Action Plan. Overall, these results indicate that appropriate macrolide use involves a review of their use for common cold along with appropriate evaluation of their long-term use for skin and allergic diseases. They also indicate the need for further fact-finding studies and ongoing AMR measures.


Ethics
As this was a database study that did not deal with the personal information of patients, ethical approval was waived.

Study design and data source
This retrospective observational study used administrative claims data from JMDC Corporation (Tokyo, Japan), covering January 2013 to December 2018. The JMDC database is a fully anonymized, nationwide electronic database based on receipts (inpatient, outpatient, and prescription) from multiple health insurance companies. The database covers approximately 2% of the Japanese population and 10% of health insurance group subscribers, with a cumulative total of 14 million subscribers as of April 2022 [16,17]. The age of enrolled people ranges from 0 to 75 years, but the greatest number of people are aged 15-65 years and belonged to the working population. The data are divided into multiple data sets, including patient information (patient ID, date of birth, gender), facility information (medical facility ID, number of beds code, department code, management entity code), receipt (patient ID, year and month of treatment, medical facility ID, department code), injury and disease information (patient ID, year and month of treatment, medical facility ID, International Classification of Diseases, 10th Revision [ICD-10] code), drug information (patient ID, medical treatment date, medical facility ID, Anatomical Therapeutic Chemical Classification System [ATC] code, dosage and number of days per prescription, route of administration), and prescription status (inpatient or outpatient). As antimicrobials prescribed in Japan mainly include oral antimicrobials and a large proportion of these prescriptions are for outpatient use [10], only the codes for outpatient prescriptions and oral antimicrobials were extracted in this study. Systematic classification of antimicrobials and the names of their components were based on the ATC system (https:// www.whocc.no/atc_ddd_index/) of the WHO.
To investigate the use and changes in macrolides before and after the Action Plan, the types of macrolides and names of diseases (e.g., International Statistical Classification of Diseases, 10th revision [2009]) were analyzed. As the population in the JMDC database is increasing annually and it is difficult to compare annual usage by number of cases, we used proportions for comparison, taking the number of annual prescriptions of macrolides as the denominator [17,18].
The macrolides were effective against most gram-positive cocci, some gram-negative rods (Bordetella pertussis, Helicobacter pylori, Campylobacter jejuni, etc.), atypical pathogens (Mycoplasma pneumoniae, Legionella pneumophila, Chlamydophila pneumoniae, Babesia microti, Ureaplasma spp., etc.), and non-tuberculous mycobacteria [19][20][21]. The required treatment duration of the antimicrobial therapy varied greatly depending on the disease, severity, immunodeficiency, and other background conditions; however, the optimal duration of therapy has not been determined for some diseases. In severe M. pneumoniae pneumonia and L. pneumophilia pneumonia in immunocompromised individuals, macrolide usage is recommended for up to 14 days [22,23]. Therefore, in this study, we defined acute diseases as those for which the number of prescribed days was less than 14 and chronic diseases as those for which the number of prescribed days was more than 14 days.

Statistical analysis
First, we determined the proportion of prescriptions for all antimicrobials and for macrolides from 2013-2018. Next, basic information regarding whether macrolides were prescribed in the 3 years before and after the Action Plan (2013-2015 and 2016-2018) was obtained. Finally, we identified the names of diseases for which macrolides were prescribed in the 3 years before and after the Action Plan, separately for acute and chronic diseases.
The median and interquartile range (IQR) were calculated for continuous variables, and percentages (%) were determined for categorical variables. For Figs 1B and 2, the Cochran-Armitage trend test was performed. All analyses were performed using the Stata/MP 17.0 software (StataCorp LLC, College Station, TX, USA).
As the objective of this study was to determine the epidemiology of macrolide prescriptions, only descriptive epidemiology was performed without statistical evaluation, because the sample size in this study was large and could easily reach statistical significance.  Clarithromycin accounted for the largest proportion (more than 60%) in all years. The proportion of prescriptions for clarithromycin was significantly decreased (p<0.001), whereas that for azithromycin, roxithromycin, and erythromycin was significantly increased (p<0.001).

Changes in the proportion of macrolide prescriptions by age from 2013 to 2018
The number of prescriptions for macrolides from 2013 to 2018, broken down by age group, is shown in Fig 3. Prescriptions for clarithromycin accounted for approximately 60% of the total and were among the highest in all age groups.
In age groups of 0-3 and 19-29 years, in which clarithromycin was prescribed at less than 60%, relatively higher prescriptions of erythromycin (19.4%) and roxithromycin (14.3%) were found. Azithromycin was prescribed relatively frequently in the age group 19-29 and 30-39 years, and exceeded 25%.

Basic information on macrolide prescriptions in the 3 years before and after the Action Plan
The characteristics of the patients and facilities at which macrolides were prescribed during the entire study period (n = 13,657,028), 2013-2015 (n = 5,242,369), and 2016-2018 (n = 8,414,659) are shown in Table 1. Overall, 6,505,157 (47.4%) of patients were male, with a median (IQR) age of 39 (16-54) years. Dividing the patients into 10 groups based on age, the groups in their 30s and older (excluding the 70-75 year age group) accounted for more than 10%, with the 50-59 years group accounting for the largest number of cases (2,276,643; 17.1%). Internal medicine was the most common department to prescribe (6,889,473 cases; 50.4%), followed by otolaryngology with 1,216,313 cases (8.9%), and pediatrics with 907,866   Comparisons of the proportion of prescriptions between 2013-2015 and 2016-2018 showed a decrease in the 0-3, 4-6, and 7-12 years age groups from 8.1%, 6.6%, and 8.7% to 6.5%, 5.4%, and 8.0%, respectively. In contrast, the proportions of prescriptions for patients aged 40-49, 50-59, and 60-69 years increased from 16.2%, 16.1%, and 11.2% to 16.9%, 17.8%, and 12.6%, respectively. The proportion of prescriptions from otolaryngology and pediatrics also decreased from 9.5% and 7.0% to 8.5% and 6.4%, respectively. Regarding the type of medical institution, prescriptions from clinics decreased from 67.0% to 64.8%, whereas those from university hospitals increased from 6.1% to 7.5%. Table 2 shows the 10 most common acute diseases for which macrolides were prescribed in 2013-2015 (n = 13,555,601) and 2016-2018 (n = 23,684,663). Clarithromycin was the most commonly prescribed macrolide for 9 of the 10 diseases on the list. Except for asthma, all were respiratory infections and eight were acute diseases. A comparison of 3 years before and after the Action Plan showed that the disease names were generally consistent, although there were some differences in the percentages and rankings of illnesses.

Epidemiology of diseases for which macrolides were prescribed in the 3 years before and after the Action Plan
A similar analysis was performed, and the 10 most common chronic diseases for which macrolides were prescribed in 2013-2015 (n = 1,793,965) and 2016-2018 (n = 3,660,871) [ Table 3]. Clarithromycin was also the most commonly prescribed macrolide for 9 of the 10 diseases, and roxithromycin was the most commonly prescribed for 1 disease. In the breakdown of diseases, in 2013-2015, five diseases were respiratory infections (chronic sinusitis, acute sinusitis, acute laryngopharyngitis, acute bronchitis, non-purulent otitis media), two were dermatologic diseases (acne vulgaris, dermatitis), two were allergic disease (allergic rhinitis, asthma), and one was an ophthalmic disease (acute atopic conjunctivitis). In 2016-2018, six diseases were respiratory infections (chronic sinusitis, acute sinusitis, acute laryngopharyngitis, acute bronchitis, chronic bronchitis, non-purulent otitis media), two were allergic diseases (allergic rhinitis, asthma), one was a skin disease (acne vulgaris), and one was an ophthalmic disease (acute atopic conjunctivitis). In each period, all the diseases were acute. In all periods, five diseases included "acute" in their name. Sinusitis was the most common acute and chronic condition in both periods.

Discussion
In this study, we analyzed Japanese social insurance data from the JMDC and clarified the epidemiology of the number of macrolide prescriptions. The number of macrolide prescriptions accounted for approximately 30% of all oral antimicrobial prescriptions; among these, clarithromycin was the most common, similar to previous reports [11,24]. Comparing the situation in other countries, among outpatient prescriptions of antimicrobials in the United States, macrolides account for 23%, and azithromycin is the most prescribed antimicrobials [25]. In Europe, intermediate-acting macrolides, mainly comprising clarithromycin, show the largest prescription rate at 58.9%, suggesting that the situation in Japan and Europe is similar [13].
Our study shows a decrease in the proportion of macrolide prescriptions from 2013 to 2018 (Fig 1B), although the overall number of cases increased each year (Fig 1A). Clarithromycin showed a decreasing trend, while azithromycin, roxithromycin, and erythromycin showed increasing trends (Fig 2). The 10 most common acute diseases for which macrolides were prescribed showed no change before and after the Action Plan. National antimicrobial sales in Japan have been reported to have decreased since 2016 [26]. Therefore, it was speculated that the decrease in overall antimicrobial use of antimicrobials for cold syndromes and other conditions due to the AMR measures may have influenced the decrease in the percentage of macrolide antimicrobials used. The reasons clarithromycin is frequently used in Japan is likely because it is a broad-spectrum antibacterial agent with few side-effects, acts for a long time in the body, and is expected to have an immunomodulating effect. Further investigation is needed to clarify the factors that contributed to the decrease in the use of macrolide antibacterial agents [11]. Current AMR measures include antimicrobial awareness surveys, surveillance of antimicrobial use, and the development of guidance and educational tools around the proper use of antimicrobials for primary care physicians [27]. However, there is still no approach targeting reduction of macrolides. To further rationalize macrolide prescriptions, several different and specific approaches are needed. The first is to reduce the use of macrolides against common cold (acute bronchitis, acute laryngopharyngitis, acute sinusitis, acute pharyngitis, acute upper respiratory tract inflammation, acute bronchiolitis, and acute nasopharyngitis). A previous study defined diseases that required the use of macrolides. Moreover, the study classified allergic rhinitis, asthma, acute bronchitis, influenza, non-purulent otitis media, and viral upper respiratory tract infections as those that did not require them. Therefore, it reported that the proportion of diseases for which macrolides should be used as first-line therapy was only 5% [25]. As shown in Table 2, macrolides are commonly used for common cold; therefore, refraining from using macrolides for treating common cold is one possible approach to reduce unnecessary consumption.
The second approach is to review the use of long-term use macrolide prescriptions. As shown in Table 3, similar to the acute phase, use for common cold accounted for half of most prescribed diseases, but macrolides were also used for dermatologic diseases and allergic diseases. Macrolides act against a wide range of bacteria, and 14-and 15-membered macrolides are also known to exert immunomodulatory effects [28]. After reports of long-term low-dose erythromycin use in patients with diffuse panbronchiolitis in Japan, small-dose long-term macrolide therapy was thought to be effective for other chronic airway diseases [29]. Macrolide therapy has been recommended for chronic sinusitis, bronchial asthma, bronchiectasis, and chronic obstructive pulmonary disease in other articles and guidelines, and has been established as a useful therapeutic option [28,[30][31][32]. Furthermore, explanations of problems associated with long-term administration are limited to descriptions related to monitoring adverse effects and the possibility of drug resistance; but these have not been adequately discussed. The macrolide resistance rate against Streptococci, Mycoplasma, and the Mycobacterium avium complex is increasing in many countries [33][34][35][36][37][38][39][40]. Moreover, macrolide resistance affects treatment prognosis, especially in non-tuberculous mycobacteria where macrolides are the firstline or key drugs [21,39,40]. In addition, previous reports have suggested that in patients with bronchiectasis and non-cystic fibrosis, long-term treatment with erythromycin may alter the oropharyngeal microflora and increase the level of antimicrobial resistance [41]. In sub-Saharan Africa, a 4-year period of twice-yearly mass distribution of azithromycin to preschoolers was reported to increase resistance rates to azithromycin as well as non-macrolide antimicrobials [42]. There are concerns that even long-term administration of small doses of macrolides like clarithromycin may pose a similar risk, indicating the need for further studies. To minimize emergence of resistance, the evidence for diseases requiring low-dose long-term administration should be reaffirmed, and physicians should be educated avoid prescribing for prolonged cough only.
The third approach involves evaluation of macrolides for treating acne vulgaris, as shown in Table 3, where the use of roxithromycin for acne vulgaris was found to be among the top 10 most common diseases for which macrolides were prescribed for long-term. As of September 2022, roxithromycin was not marketed in the United States and was only available in some countries, including Australia, France, and Germany. In Japan, roxithromycin is also indicated for dermatologic infections, chronic pyoderma, acne vulgaris, laryngopharyngitis, acute bronchitis, pneumonia, otitis media, and sinusitis. Oral antimicrobial therapy is strongly recommended for inflammatory skin rashes in the 2016 acne vulgaris treatment guidelines of the Japanese Dermatological Association [43]. In contrast, oral retinoids are the first choice of treatment for severe acne vulgaris in the US and EU guidelines; however, these are not approved in Japan owing to their serious side effects, including teratogenicity [44,45]. In case of regulatory approval of oral retinoids by further clinical trials, use of systemic antimicrobials including macrolides may decrease. Furthermore, azithromycin and erythromycin are recommended in the guidelines for moderate to severe acne vulgaris, which is refractory to local therapy [44]. Although azithromycin has fewer side effects than tetracyclines, macrolides should only be considered when tetracyclines are unavailable. Moreover, erythromycin use should be limited considering the development of resistance. Furthermore, systemic antimicrobials should be administered for as short a time as possible, with re-evaluation every 3-4 months to prevent the acquisition of resistance [44]. Based on our data, the severity of acne vulgaris and the history of tetracycline administration could not be evaluated. These points may serve as potential interventions for the ASP in future.
This study has several limitations. First, although this study analyzed a large dataset of 13.6 million prescription records, the JMDC database is based on the health insurance of employees of large companies and their families; therefore, the number of subjects younger than 15 years of age and older than 65 years of age is relatively small and the results may not be generalizable. Second, because it is a retrospective, administrative claim database, it lacks clinical information such as symptoms, severity, pathogens, drug allergies, laboratory data, and adherence to antimicrobials. Furthermore, it does not verify whether the disease name is consistent with the actual diagnosis. These shortcomings have also been pointed out in previous studies using JMDC data [17,46,47]. We believe that this issue needs to be addressed in future because there is no medical database with sufficiently verified diagnostic and clinical information in Japan. Third, as the database was integrated by linking the dataset, there may not be a single disease registered at the time of prescribing the macrolide antimicrobials. Furthermore, if a drug other than macrolide antibacterial agents is prescribed at the same visit, several disease names are added to the receipt. Therefore, unrelated comorbidities such as diabetes, hypertension, and insomnia are also added to the list of disease names, making it difficult to determine whether macrolide antimicrobials were truly used. We evaluated the 10 most common diseases for which macrolides were prescribed to avoid this problem. Fourth, the results (except for Tables 2 and 3) use the number of prescriptions as the evaluation index and do not consider the number of days of prescription. Thus, even if the total number of prescription days is the same, the number of prescriptions increases if there are multiple prescriptions for a short period, which introduces a difference in the results. Previous studies have also used number of cases; thus, we used the number of cases in the present study for comparison with the past results [17,25].
Despite several limitations, the strengths of this study are that it identifies the epidemiology of macrolide prescriptions and the names of diseases for which macrolides are used by dividing them into acute and chronic based on the number of prescription days. Furthermore, it identifies possible intervention points for appropriate macrolide use in the future. We believe that AMR measures, including further rationalization of macrolide use, are needed to efficiently cure patients, reduce AMR, and reduce harm caused by unnecessary use of antimicrobials [48]. Overall, our results are important in terms of considering the potential of such measures.
In conclusion, macrolides account for approximately 30% of all oral antimicrobials prescribed in Japan, with clarithromycin being the most used. To reduce the use of macrolides, reviewing their use for treating common cold and reevaluating their long-term use for allergic and dermatologic disease may be necessary. These findings are important for appropriate macrolide use in the ASP. However, further research is needed on the actual use of macrolide antimicrobials and the ongoing AMR measures.